MPN Word of the Month: Platelets

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As we know, myeloproliferative neoplasms (MPNs) are a group of blood cancers that involve the overproduction of blood cells in the bone marrow. These conditions primarily include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). One of the primary features of certain MPNs, particularly essential thrombocythemia, is the abnormal production and function of platelets, that help with blood clotting and maintaining vascular integrity. Understanding the relationship between platelets and MPNs is crucial for diagnosing,
monitoring, and managing these disorders.

What Are Platelets?

Platelets, also known as thrombocytes, are small, disc-shaped cell fragments in the blood. Produced in the bone marrow by megakaryocytes, platelets are essential for hemostasis—the process that prevents excessive bleeding when blood vessels are injured. When a blood vessel is
damaged, platelets adhere to the site of injury, coagulate to form a plug, and interact with clotting factors to stabilize the clot, preventing further blood loss.

How Do Platelets Work In MPNs?

In MPNs, the bone marrow exhibits uncontrolled proliferation of hematopoietic stem cells, leading to the overproduction of various blood cells, including platelets. This dysregulation can significantly impact platelet function and count, resulting in both hemorrhagic and thrombotic complications.

Platelets in Essential Thrombocythemia (ET)
Essential thrombocythemia is characterized by an excessive production of platelets due to  mutations in genes such as JAK2, CALR, or MPL. In ET:

● High Platelet Counts: Patients often present with elevated platelet counts, sometimes exceeding one million platelets per microliter of blood. Despite the abundance of platelets, they may not function normally, leading to an increased risk of clotting (thrombosis) and bleeding (hemorrhage).
● Thrombotic Risk: Abnormally high platelet counts increase the likelihood of clot formation within blood vessels, potentially leading to complications such as stroke, heart attack, deep vein thrombosis (DVT), and pulmonary embolism.
● Bleeding Risk: Interestingly, patients with extremely high platelet counts can also experience bleeding issues. This is because the overproduction of platelets can lead to a depletion of von Willebrand factor (vWF), which is necessary for platelet adhesion,

Platelets in Polycythemia Vera (PV)
In PV, there is an overproduction of red blood cells, often accompanied by increased platelets and white blood cells:

● Platelet Dysfunction: Although the platelet count in PV is usually elevated, platelet function can be abnormal. This dysfunction can result in an increased risk of thrombosis even though there is a high platelet count.
● Thrombotic Events: Similar to ET, patients with PV have a higher risk of blood clots because the not only is there an increase in blood viscosity (from elevated red blood cell mass) there is also altered platelet function.

Platelets in Myelofibrosis (MF)
Myelofibrosis is marked by the replacement of bone marrow with fibrous tissue, impairing normal blood cell production:

● Variable Platelet Counts: Patients with MF may have either low (thrombocytopenia) or high (thrombocytosis) platelet counts, depending on disease progression and bone marrow function.
● Abnormal Platelet Function: Regardless of the platelet count, platelet function is often compromised, which leads to a higher risk of both bleeding and clotting events.

Platelets in Diagnosis and Management
The evaluation of platelet count and function is an important part of diagnosing and managing MPNs. Laboratory tests commonly used include:

● Complete Blood Count (CBC): To assess platelet count, red blood cell mass, and white blood cell count.
● Bone Marrow Biopsy: To examine marrow architecture and megakaryocyte proliferation, providing insight into the degree of myeloproliferation.
● Genetic Testing: To identify mutations in JAK2, CALR, and MPL genes, which are associated with different MPNs.
● Platelet Function Tests: In some cases, platelet aggregation studies may be used to evaluate platelet function, especially if bleeding complications are present.

The primary goal in managing MPNs is to minimize the risk of thrombotic and hemorrhagic events. Several treatment strategies are used to address abnormal platelets such as cytoreductive therapies, antiplatelet agents, JAK2 inhibitors, and close monitoring of blood counts.

Platelets play a central role in the diagnosis, progression, and care of myeloproliferative neoplasms. Understanding the complex interactions between platelets and MPNs is crucial for effective diagnosis, risk assessment, and management of these disorders. With appropriate
monitoring and individualized treatment strategies, the risks associated with abnormal platelet activity in MPNs can be managed, improving patient outcomes. For more information about MPNs visit our website at www.mpnadvocacy.com.

Choosing the Right JAK Inhibitor for Effective Myelofibrosis Treatment

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By Jordyn Sava
Fact checked by Sabrina Serani

With 4 JAK inhibitors approved in the US and additional agents in development, it is an exciting time for the field of myeloproliferative neoplasms (MPNs). Now, experts face the challenge of determining which treatment is best for each patient.

Ruxolitinib (Jakafi), an established JAK inhibitor, was first approved by the FDA in 2011,1 showing clear survival benefits. This was followed by the FDA approvals of fedratinib (Inrebic) in 2019,2 pacritinib (Vonjo) in 2022,3 and momelotinib (Ojjaara) in 2023.4

“Each [JAK inhibitor has] their place depending on the patient’s blood counts and other clinical factors,” explained Prithviraj Bose, MD, in an interview with Targeted OncologyTM.

With multiple JAK inhibitors available to choose from, a tailored approach ensures that each patient’s specific disease characteristics and comorbidities are considered to maximize efficacy and minimize toxicity during treatment.

In the interview, Bose, professor in the Department of Leukemia at MD Anderson Cancer Center, discussed the multiple JAK inhibitors available for the treatment of patients with MPNs.

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Ruxolitinib Could Be Useful in MF Care

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Leonardo Jaimes, MD

Ruxolitinib appears to produce durable responses and minimal adverse effects in patients with myelofibrosis (MF) in a real-world setting, according to a recently published study in Cancer.

Since its US Food and Drug Administration approval over a decade ago, the JAK1/JAK2 inhibitor ruxolitinib has become one of the most commonly used drugs for the management of MF-associated symptoms, the study team noted. Its approval is based on the results from the COMFORT study, which included only intermediate-2 and high-risk patients, they continued.

“However, intermediate-1 risk patients may carry a significant burden of disease and are increasingly treated with ruxolitinib in the real-life setting. Moreover, in some European countries (e.g., Germany) approval of ruxolitinib is not restricted to higher risk patients but rather to those with symptomatic disease (even when intermediate-1 or low risk),” the authors wrote.

Given the lack of studies investigating the effectiveness and safety of ruxolitinib in an intermediate-1 risk patient population and the small cohorts and short follow-up times used in previous studies, the research team aimed to assess the drug in a real-world clinical practice context.

The retrospective study included data from over 1000 patients with MF who had received ruxolitinib since 2013. Approximately 56% of the patients were intermediate risk-1.

The authors observed a 26% spleen response rate after six months of ruxolitinib in the intermediate risk-1 population and a 68% symptom response rate. Both rates were slightly inferior in patients with intermediate risk-2.

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Hypomethylating Agents Show Promise in Myelofibrosis Progression After alloHCT

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Andrea S. Blevins Primeau, PhD, MBA

Donor chimerism was restored with hypomethylating agent (HMA) treatment among some patients with myelofibrosis (MF) who relapsed after allogeneic hematopoietic cell transplantation (alloHCT), according to a small retrospective published in the journal Transplantation and Cellular Therapy.

These data suggest that HMA “is an option for patients in the future,” the researchers wrote in their report. “By promoting restoration of donor chimerism and clearance of pre-alloHCT somatic mutations, HMAs offer a capable therapeutic strategy for improving outcomes in this challenging patient population.”

In the single-center, retrospective study, the researchers analyzed data from the electronic health records of 12 patients with MF who relapsed after alloHCT between 2020 and 2023 and were subsequently treated with an HMA.

The median age of the cohort was 61 years and 33% of patients had primary MF, 41.7% had post-essential thrombocythemia MF, and 25.0% had post-polycythemia vera MF.

There were 92% of patients with disease classified as intermediate-2/high-risk by the Dynamic International Prognostic Scoring System (DIPSS) and 83% were considered high or very high risk by the Molecular International Prognostic Scoring System (MIPSS70+). There were 66.7%, 25.0%, and 16.7% of patients with JAK2, MPL, or CALR driver mutations, respectively, at diagnosis.

After transplantation, 99.9% of patients achieved donor chimerism at day 30 and 96.6% at day 100. Patients relapsed after alloHCT within a median of 282.5 days (range, 96-2388 days). The median donor chimerism before initiating an HMA was 57.82%.

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Shear Wave Elastography Distinguishes Myelofibrosis From Other MPNs

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Sep 25, 2024

 

Liver and spleen shear-wave elastography helped distinguish patients with myelofibrosis from healthy controls and those with essential thrombocytopenia, according to findings published in the Journal of Ultrasound. This suggests that the technique may help diagnose myeloproliferative neoplasms.

Researchers added that liver stiffness and spleen stiffness appeared to be linked with bone marrow fibrosis.

“Vibration-controlled transient elastography (VCTE) has proven to be a valuable tool in providing prognostic and staging information in patients with liver disease, greatly reducing the need for liver biopsy,” Vito Sansone, MD, Student, and colleagues wrote. “Spleen stiffness, similarly, has proven useful as a surrogate marker of portal hypertension. To date, however, the role of any of these techniques in the work-up of MPNs has not been established. …This study aims to investigate if values of liver and spleen stiffness measured with shear-wave elastography could help to differentiate MPNs from healthy controls and if there are significant differences in values of liver stiffness and spleen stiffness.”

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HTR1B Expression and Thrombosis in Patients With Myeloproliferative Neoplasms

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Vicki Moore, PhD

In this retrospective study, the researchers evaluated expression levels of HTR1B based on messenger RNA from peripheral blood mononuclear cells obtained from patients with newly diagnosed MPN, in addition to conducting other analyses. The researchers had a goal of evaluating possible differences in expression of this gene across MPN subtypes.

There were 85 patients with newly diagnosed MPN included in the analysis, with a median age of 57 years (range, 23-80). Among these patients, 28 had polycythemia vera (PV), 25 had essential thrombocythemia (ET), and 32 had primary myelofibrosis (PMF). Additionally, comparisons of HTR1B expression included 6 healthy volunteers.

Across MPN subtypes and control individuals, the expression of HTR1B did not significantly differ (P =.3089). However, there was large variation observed in expression levels. The researchers further examined expression levels in the context of other patient factors, including based on whether patients had a thrombotic or non-thrombotic history.

A total of 32 patients were considered to have thrombotic MPNs and 53 patients were considered to have nonthrombotic MPN, with median ages of 57 years in each group. Levels of HTR1B expression were significantly different when analyzed across groups organized by thrombotic MPN, nonthrombotic MPN, or status as control individuals.

The level of HTR1B expression appeared highest among patients with thrombotic MPNs, while levels appeared to not be significantly different between patients with nonthrombotic MPNs and control individuals. Among patients with thrombotic MPNs, there was no statistically significant difference observed in the level of fold-change in HTR1B expression by MPN subtype.

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Researchers Identify INCA033989 as a Potential Treatment for Myeloproliferative Neoplasms

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By Alexandra Gerlach, Associate Editor

Data from a study published in Blood demonstrates the therapeutic potential of INCA033989 as the first targeted therapy for myeloproliferative neoplasms (MPNs) that does not interfere with normal blood cell production. Existing therapeutic options for MPNs are effective at symptom management but have high discontinuation rates due to resistance and inadequate drug tolerability. The development of INCA033989 opens pathways to more effective, targeted options with disease-modifying potential without any negative impact on surrounding blood cells.1

The development of INCA033989 has positive implications for the evolving treatment landscape of patients with MPNs. Image Credit: © Anna – stock.adobe.com

MPNs are a group of malignancies characterized by the overproduction of red and white blood cells and is an umbrella for 6 different disease types: myelofibrosis (MF), essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Calreticulin (CALR) mutations are responsible for disease development in 20% to 30% of patients with MPNs, which can be either insertions or deletions in exon 9 of CALR. The mutated CALRprotein (mutCALR) is responsible for the stable interaction with thrombopoietin receptors (TPO-R), which are crucial for controlling blood cell production.2,3

Janus kinase (JAK) inhibitors, such as ruxolitinib (Jakafi; Incyte Corp), are the recommended treatment options for patients with MF or other MPNs; however, they are associated with adverse effects (AEs), namely grade 3 or 4 anemia. INCA033989 is a high affinity, fully human immunoglobulin G1 selective monoclonal antibody targeting mutCALR-driven oncogenesis to suppress TPO-R signaling, thereby preventing the proliferation and progression of disease. According to data from the original study announcing the development of this agent, there was an observed synergism between INCA033989 and ruxolitinib which resulted in the inhibition of cell proliferation and indicated the ability of INCA033989 to enhance the efficacy of ruxolitinib.3,4

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New Trial Sets Out to Test Treatment for Early Primary MF

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Özge Özkaya, MSc, PhD

A new randomized, double-blind, placebo-controlled, phase 3 clinical trial assessing the safety and efficacy of ropeginterferon alfa-2b, a new-generation pegylated interferon-based therapy, in patients with early and lower-risk primary myelofibrosis (MF) is now open.

The trial aims to recruit 150 such patients who are at least 18 years of age and will receive either up to 500 μg of subcutaneous ropeginterferon alfa-2b or a placebo every 2 weeks until 56 weeks.

The primary endpoints of the trial include clinically relevant complete hematologic response as measured by platelet count, white blood cell count, hemoglobin levels in peripheral blood, absence of thrombotic events, and no progression to acute myeloid leukemia, and symptom endpoint.

Secondary endpoints include bone marrow response, event-free survival or progression-free survival, molecular response in driver or relevant coexisting gene mutations, and safety.

“The study will provide important data for the treatment of early/lower-risk [primary] MF for which an anti-clonal, disease-modifying agent is highly needed,” the researchers wrote in an article that they published in the journal Annals of Hematology, which contains the details of the trial design.

The trial is not yet recruiting participants. It is estimated to start in October 2024 and be completed in August 2027.

Previous research has shown that ropeginterferon alfa-2b has favorable pharmacokinetics and safety profiles and requires less frequent injections than previous formulations of pegylated interferon alfa, the researchers noted.

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Korean Study Finds DOAC Use “Seems Effective” in Patients With MPNs

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September 25, 2024

Author(s): Mary Caffrey

A study based on a decade’s worth of Korean insurance data found that use of direct oral anticoagulants (DOACs) to address atrial fibrillation and venous thromboembolism in patients with myeloproliferative neoplasms (MPNs) is effective, with acceptable bleeding risk.

Patients with Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) face an elevated risk of arterial and venous thrombosis, due to the increased production of mature myeloid blood cells caused by their condition.1 The increased morbidity and mortality caused by atrial fibrillation (AF) and venous thromboembolism (VTE) among patients with MPNs has led the American College of Cardiology and the American Heart Association, among others, to recommend direct oral anticoagulants (DOACs) to prevent blood clots and reduce the risk of major cardiovascular events in patients with MPNs.2

However, a group of authors from Korea, writing in Cancer Research and Treatment, note that the actual amount of evidence regarding the use of DOACs in patients with MPNs is limited. This week, they published a study based on a decade’s worth of Korean insurance data. Based on an analysis of records from 368 patients with MPNs, they concluded that use of DOACs in this population “seems effective with an acceptable bleeding risk.”3

The authors write that a prior study, with very limited data, found the 1-year cumulative incidence of thrombosis was 5.5% and bleeding was 12.3% among patients with MPNs taking DOACs.3 They note their study population involved patients who were somewhat older (average age, 74 years) and had a higher CHA2DS2-VASc score, which evaluates a patient’s risk based on the presence of congestive heart failure, hypertension, age, diabetes status, history of stroke or transient ischemic attack, and vascular disease; risk is doubled if the patient is 75 years or older.

The Korean study was based on data from the Health Insurance Review and Assessment Service, which has information on inpatient and outpatient care for 50 million Koreans. Investigators pulled patient data from the period of January 1, 2011, to January 1, 2021. The cohort of 368 patients had the following characteristics:3

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Bose’s Guide to Ruxolitinib, Fedratinib, Pacritinib, and Momelotinib

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By Prithviraj Bose, MD

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

Transcription:

0:09 | We have 4 JAK inhibitors approved for the treatment of myelofibrosis in the US. Important to note, pacritinib [Vonjo] is not approved outside the US. There is obviously a lot to say on this topic, especially, ruxolitinib [Jakafi] was approved in 2011, fedratinib [Inrebic] in 2019 and then pacritinib and momelotinib [Ojjaara], more recently, 2022 and 2023. But I think I will just hit some high points.

0:36 | So for ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well in order to get the benefit that you are seeking. The dose can get compromised by cytopenias.

1:29 | That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets than 50, and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they sort of have their place more in that cytopenic population, which could be frontline, or, more commonly, second-line, after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

2:12 | I will just say 1 last thing about fedratinib, which was the second one approved. This is a good drug, perhaps as good as ruxolitinib from an efficacy stand point, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in second-line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high level points about the 4 drugs.

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